[Oxo-4-4H-[1]-benzopyran-8-yl]alcanoic acids, salts and derivatives, their manufacture and medicines containing them

ABSTRACT

The invention concerns [oxo-4-4H-[1]-benzopyran-8-yl]-alcanoic acids and their derivatives, their manufacture, represented by the formula. ##STR1## where AR is hydrogen, a phenyl radical which may or may not be substituted thenyl, furyl, naphthyl, a lower alkyl, cycloalkyl, aralkyl radical; B is a linear or branched lower alkyl radical, either saturated or ethylinically unsaturated; R 1  is hydrogen or a phenyl radical; X is hydrogen or a lower alkyl or alkoxy radical and n=1, as well as salts, esters, aminoesters and amides. 
     Compounds and their derivatives may be used as medicines, in particular in the control of tumors.

This is a continuation of application Ser. No. 669,037 filed Nov. 6,1984, now U.S. Pat. No. 4,602,034, which is a continuation of Ser. No.442,191, filed Nov. 15, 1982, abandoned.

The invention concerns [oxo-4-4H-[1]-benzopyran-8-yl]alkanoic acids,certain of their salts and derivatives, their preparations, intermediatecompounds necessary to produce them and some medicines containing them.

These compounds are represented by the formula: ##STR2## where AR ishydrogen, a phenyl radical which may or may not be substituted thenyl,furyl, naphthyl, a lower alkyl, cycloalkyl, aralkyl radical; B is alinear or branched lower alkyl radical, either saturated orethylinically unsaturated; R₁ is hydrogen or a phenyl radical; X ishydrogen or a lower alkyl or alkoxy radical and n=1, as well as theiralkaline metal salts, in particular sodium salts.

These acids may be prepared in accordance with the invention by one orother of the methods described below, which enable them to be preparedat good yield levels.

When it is the case that in formula 1 for the acids: n=1 and B=CH₂, theacids are prepared by hydrolysing a nitrile of the formula: ##STR3##where AR, X and R₁ have the same meanings as before, in particular in ahot acid medium. The above nitriles are obtained by treatingbromomethyl-8 benzopyranone-4 having the formula: ##STR4## where X, ARand R₁ have the same meanings as before, with an alcaline cyanide. Thesenitriles are new intermediate compounds and, in this respect, are partof the invention.

When in formula I for acids: n=1 and B=CH=CH, it is also possible toreact a bromomethyl-8 benzopyranone-4 of formula (III) withhexamethylenetetramine, and then condense the aldehyde obtained. When informula I for the acids: n=1 and B=CH=CH, concentration is carried outwith acetic anhydride in the presence of sodium acetate.[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]carboxaldehyde is a newintermediate product. When AR=H and R₁ =phenyl, the aldehyde obtained iscondensed with tetraethyl diethylaminomethylenediphosphonate in thepresence of sodium hydride. The corresponding acid is obtained byhydrolysis. [oxo-4-phenyl-3-4H[1]-benzopyran 8-yl] is new and is anintermediate product.

Where n=1 and B is a branched alkyl radical, in particular ##STR5## theintroduction of the branch is performed by converting the acid to anester and then to the malonate which is alkylated and then hydrolised inthe corresponding acid. When n=1 and B is CH₂ --CH₂, bromomethyl-8benzopyranone-4, having formula III, is initially made to react with thediethyl malonate in the presence of a base such as sodium hydride, thesodium alcoholate or sodium in an appropriate solvent. The substitutedmalonate obtained is then hydrolysed in the corresponding acid.

Malonates represented by the formulae: ##STR6## where X, AR and R₁ havethe same meanings as before, are new intermediate compounds in thepreparation of compounds covered by the invention.

Salts of alkaline metals from acids coming under the invention, inparticular sodium salts are obtained by neutralising the above acids.

Derivatives of acids in the form of esters of the formula: ##STR7##where AR, B, X, R₁ and n have the same meanings as previously, R₂ beinga lower alkyl or lower hydroxyalkyl radical prepared by esterificationof the previous acids.

Aminoesters as in formula VI, where AR, B, R₁, X and n have the samemeanings as before, R₂ being a lower dialkyl, lower dialkyl amino loweralkyl or morpholinoethyl radical are obtained by condensing thepreceding acids with a halogen, preferably chloralkylaminodialkyl.

The amides derived from the acids represented by the formula: ##STR8##where AR, B and n have the same meanings as previously, R₃ being adialkylaminoalkyl radical are obtained by condensing the esters of theacids having formula VI where R₂ is a lower alkyl radical, with adialkylaminoalkylamine.

The salts of esters, aminoesters and amides with mineral or organicacids that are acceptable in human therapy are easily obtainable andsimple to use.

The acids and their derivatives covered by the invention, and moreparticularly the substance in example 3 have exhibited worthwhilepharmacological properties as anti-tumour drugs. Pharmacological testshaving been carried out on several types of tumours. Examples are:

P 388 lymphocytic leukemia: a test was carried out on CFD1 strain mice.0.1 ml of ascetic fluid containing 10⁶ cells are implantedintraperitonally at day zero. The animals were treated i.p. from day 1to day 9, with one injection per day and weighed on day 1 and day 5(toxic day). The control value (median survival time) accepted was 9-14days. Six mice were used per test (one test=one dose). A difference inweight of more than 4 g at day 5 between the test mice and the controlmice was an indication of toxicity. The following ratio was determined:##EQU1## A T/C <85% indicates toxicity. T/C between 85 and 120%indicates non-activity. T/C >120% indicates activity.

In this test, the substance in example 3, administered at the rate of200 mg/kg gave T/C=195. Under the same conditions, 5-Fluorouracile, ananti-metabolite class of anti-cancer substance (antipyrimidine) gaveT/C=185.

Carcinoma 38 of the colon: This test was carried out on B6C3F1 or BDF1strain mice. A fragment of 70 mg of tumour was implanted sub-cutaneouslyat day zero. The animals were treated i.p. from day 2 to day 9 (2injections). The accepted control value is the mean tumour weightsituated between 400 and 2000 mg. 10 mice were used per test. Thefollowing ratio was determined: ##EQU2## Activity is indicated by T/Cless than 42. As an example, the substance in example 3 gave thefollowing results in the three cases: Administered doses T/C 200 mg/kg:10; 200 mg/kg: 0; 50 mg/kg: 38.

The medicine contains, as its active ingredient, a compound covered bythe invention, associated with an acceptable vehicle or pharmaceuticalexcipient, in a suitable form for oral, parenterale or intravenousadministration.

Unit doses may be sugar-coated pills, tablets, capsules, gellules,phials or bottles. These dosage forms contain between 50 and 1000 mg ofactive ingredients.

As an example, the following compositions are to be found: Coated pill:active ingredient: 100 mg. Excipients: magnesium stearate, lactose,talcum, starch, alginic acid, hydroxypropylcellulose. Bottle: activeingredient: 1000 mg in freeze-dried form desolved in 20 ml of water foradministration by injection.

Examples are given below illustrating the invention. They are notexhaustive.

EXAMPLE 1 [oxo-4-phenyl-2-4H[1]-benzopyran-8-yl]acetonitrile C₁₇ H₁₁ NO₂(formula 1), MW=261.26

A solution of 31 g (0.476 mole) of potassium cyanide in 150 ml of wateris heated to 60°-70° C. A suspension of 75 g (0.238 mole) ofbromomethyl-8-phenyl-2-4H-[1]-benzopyran-4-one in 965 ml of boilingethanol is then added in fraction, and then boiled for 3 hours with areflux condensor. The mixture is filtered hot and filtrate is placed ina refrigerator for 48 hours. The precipitate formed is centrifuged anddried. Weight obtained: 42 g (Yield 67.5%), IR: νc=0: 1640 cm⁻¹. δNMR(DMSO) compared with T.M.S. 2H at 4.45 (singlet), 1H at 7.05 (singlet),8H from 7.15 to 8.6 (solid).

EXAMPLE 2 [oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-acetic acid C₁₇ H₁₂ O₄(formula 2) MW=280.27

42 g (0.16 mole)of oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetonitrileare added to a mixture consisting of 117 ml of acetic acid and 117 ml ofwater. 117 ml of concentrated sulfuric acid are then added slowly andthe mixture is refluxed for 31/2 hours. After cooling, it is poured into1.5 liters of iced water. The precipitate formed is centrifuged, andtaken up in a 5% sodium bicarbonate solution at 50°-60° C. Theremaining, slightly insoluble matter is filtered out and the filtrateacidified with concentrated hydrochloric acid. The beige-colouredprecipitate is centrifuged, washed in water, dried and re-cristallisedin alcohol. Weight obtained: 39.7 g (Yield 88.6%), MP_(G) : 234° C., IR:ν=0 (pyrone): 1640 cm⁻¹ ; ν=0 (acid): 1720 cm⁻¹, NMR (DMSO) δ en ppmcompared with T.M.S. 2H at 4 (singlet), 1H at 7 (singlet), 8H from 7.3to 8.3 (solid), 1H at 12.6 (exchangeable) with D₂ O).

    ______________________________________                                        Weight analysis                                                                            C %         H %    0 %                                           ______________________________________                                        Calculated:  72.84       4.32   22.84                                         Found:       72.73       4.36                                                 ______________________________________                                    

EXAMPLE 3(diethylamino-2-ethyl)[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl-]acetateC₂₃ H₂₅ NO₄ (formula 3) MW=379.39

21 g (0.075 mole) of [oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl-]acetic acidare dissolved in 1.2 liters of ethanol. The mixture is removed from theheat and a solution of 4.2 g (0.075 mole) of potassium hydroxide in 75cm3 of ethanol is added. This is stirred for 30 minutes atroom-temperature, the alcohol evaporated, the solid residue is driedazeotropically with benzene, after which 370 ml of acetone added, plus asolution of 11 g (0.0813 mole) of diethylamino-2-chloro-1-ethane in 37ml acetone. This is heated in a reflux condenser for four hours. Theinsoluble matter is filtered out when hot and the filtrate evaporatedunder vacuum. An oil is obtained which cristallises at roomtemperatures. IR: ν=0 (ester): 1730 cm⁻¹, ν=0 (pyrone): 1660 cm⁻¹.

Chlorhydrate: C₂₃ H₂₆ ClNO₄, MW=415.89, BP_(G) : 186° C. (isopropanol)

IR: νc=0 (ester): 1740 cm⁻¹, νc=0 (pyrone): 1660 cm⁻¹, νNH⁺ : band from2400 to 2700 cm⁻¹, NMR (CDl₃) δ in ppm compared with T.M.S. 6H at 1.2(triplet), 6H from 2.8 to 3.4 (solid), 2H at 4.15 (singlet), 2H at 4.6(triplet, 1H at 6.8 (singlet), 8H from 7.2 to 8.3 (solid), 1H at 12.6(exchangeable with D₂ O).

    ______________________________________                                        Weight analysis:                                                                        C %       H %    Cl %    N %  O %                                   ______________________________________                                        Calculated:                                                                             66.42     6.30   8.52    3.36 15.40                                 Found:    66.42     6.42   8.60    3.40                                       ______________________________________                                    

EXAMPLE 4(morpholinyl-4)-2-ethyl)[oxo-4-pphenyl-2-4H-[1]-benzopyran-8-yl]acetateC₂₃ H₂₃ NO₅ (formula 4), MW=393.38

This substance is prepared using the process in example 3 from 17.5 g(0.0625 mole) of [oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid, 3.9g (0.0625 mole) of potassium hydroxide and 11.3 g (0.0755 mole) of(chloro-2-ethyl)-4-morpholine. After isolation and treatment withgaseous HCl and re-cristallization in methanol, a white solid isobtained.

Chlorhydrate: C₂₃ H₂₄ ClNO₃, MW=429.88.

Weight obtained: 10.1 G (Yield: 37.3%, MP_(G) =193°-194° C. IR: νc=0(ester): 1740 cm⁻¹, νc=0 (pyrone): 1640 cm⁻¹, νNH⁺ : band from 2300 to2600 cm⁻¹ ;

NMR (DMSO) δ in ppm compared with T.M.S. 6H from 2.8 to 3.5 (solid), 4Hto 3.7 to 4.1 (solid), 2H at 4.2 (singlet), 2H at 4.55 (triplet), 1H at6.8 (singlet), 8H from 7.2 to 8.3 (multiplet), 1H at 12.5 (exchangeablewith D₂ O).

EXAMPLE 5 (dimethylamino-3propyle)[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetate C₂₂ H₂₃ NO₄(formula 5), MW=365.38

This substance is prepared in accordance with the process in example 3from 12.3 g (0.044 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid, 2.74 g (0.044 mole)of potassium hydroxide and 6.45 g (0.053 mole) ofdimethylamino-3-chloro-1-propane. A white solid is obtained afterprocessing. Weight obtained : 10.5 g (Yield: 65.31%), MP_(G) : 112° C.(diisopropylether).

IR: νc=0 (ester): 1735 cm⁻¹, νc=0 (pyrone): 1645 cm⁻¹ NMR (CDCl₃) δ inppm compared with T.M.S. 10H from 1.6 to 3.2 (multiplet), 4H from 3.9 to4.2 (multiplet) 1H at 6.8 (singlet), 8H from 7.2 to 8.3 (multiplet).

Chlorhydrate: C₂₂ H₂₄ ClNO₄, MW=401.88, MP_(G) : 162°-164° C. (acetone).

    ______________________________________                                        Weight analysis:                                                                        C %       H %    Cl %    N %  O %                                   ______________________________________                                        Calculated:                                                                             65.75     6.02   8.82    3.49 15.92                                 Found:    65.38     6.17   8.71    3.47                                       ______________________________________                                    

EXAMPLE 6 ethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl-]acetate C₁₉ H₁₆O₄ (formula 6), NW=308

5.1 g (0.0175 mole) of [oxo-4-phenyl-2-4H-[1]-benzopyran-8yl]acetic acidare refluxed for 7 hours in 75 ml of absolute ethanol in the presence of10 ml of concentrated sulphuric acid. The mixture is then put into arefigerator, the precipate formed is centrifuged, washed with a sodiumbicarbonate solution and water. It is recrystallized in ethanol. Weightobtained: 4 g (Yield: 74%), MP_(K) : 140° C.

IR: νc=0 (ester); 1740 cm⁻¹, νc=0 (pyrone): 1645 cm⁻¹

EXAMPLE 7 methyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl-]acetate C₁₈ H₁₄O₄ (formula 7), MW=294

This substance is prepared as in example 6 from 18 g (0.064 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid, 260 ml of anhydrousmethanol and 13 ml of concentrated sulphuric acid. Weight obtained: 18.1g (Yield: 96%), MP_(K) : 168°-169° C. (methanol).

IR: νc=0 (ester): 1735 cm⁻¹, νc=0 (lactone): 1640 cm⁻¹.

NMR (CDCl₃) δ in ppm compared with TMS. 3H at 3.8 (singulet), 2H at 4.1(singulet) 1H at 6.9 (singulet), 8H from 7.4 to 8.55 (multiplet).

EXAMPLE 8 sodium salt of [oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]aceticacid C₁₇ H₁₁ O₄ Na, (formula 8), MW=302.24

The solution is prepared of 2.1 g (0.025 mole) of sodium bicarbonate in400 ml of water. It is heated to 50° C. and 7 g (0.025 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid are added. After thesolid matter has completely dissolved, the liquid matter is allowed tocool to 30° C. and is poured into 2 liters of acetone. A white precitateforms which is centrifuged, rinsed of acetone and dried. Weightobtained: 6.2 g (Yield: 79.68%), MP_(G) =302°-304° C.(dimethylformanide). IR: νc=0 (pyrone): 1640 cm⁻¹.

    ______________________________________                                        Semihydrate MW = 311.24                                                       Weight analysis                                                                             C %    H %       O %  Na %                                      ______________________________________                                        Calculated:   65.54  3.85      23.13                                                                              7.38                                      Found:        65.60  3.88                                                     ______________________________________                                    

EXAMPLE 9 hydroxy-2-ethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetateC₁₉ H₁₆ O₅ (formula 9), MW=324.32

4 g of paratoluenesulfonic acid and 300 ml of benzene are put into areaction vessel. After elimination of the water, 28 g (0.1 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid and 300 ml ofethylene glycol are added. This is heated for four hours in a refluxcondenser to eliminate the water azyotropically. The orange solutionobtained is concentrated under vacuum and the residue poured into 1.5liter of iced water. The beige-coloured precipitate formed iscentrifuged, washed with water and recrystallized in 300 ml of ethanol.Weight obtained: 23.5 g (Yield: 72.5%), MP_(G) =158°-159° C. IR: νc=0(pyrone): 1640 cm⁻¹, νc=0 (ester): 1725 cm⁻¹, OH: 3400 cm⁻¹ : MNR(CDCl₃) δ in ppm compared with TMS.

3H from 3.45 to 3.9: (multiplet, 1H exchangeable with D₂ O), 4H from 3.9to 4.4: (multiplet), 1H at 6.8: (singular), 8H from 7.3 to 8.3:(multiplet).

    ______________________________________                                        Weight analysis:   C %    H %                                                 ______________________________________                                        Calculated:        70.36  4.97                                                Determined:        70.26  4.74                                                ______________________________________                                    

EXAMPLE 10N-[N'N'-diethylamino-2-ethyl][oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetamideC₂₃ H₂₆ N₂ O₃ (formula 10), MW=378.43

A mixture of 14.8 g (0.048 mole) ofethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetate and 6.2 g (0.053mole) of diethylamino-2 ethylamine is heated to 135°-140° C. for 5hours. The mixture is then evaporated under vacuum and the residue isdissolved in hot hexane and then recrystallized in ethyl acetate. Weightobtained: 7.5 grams (Yield: 41.28%)

IR: νc=0 (pyrone and amide): 1640.60 cm⁻¹, νNH: 3300 cm⁻¹ ChlorhydrateC₂₃ G₂₇ ClN₂ O₃, MW=414.93, MP_(G) =216°-218° C. (ethanol).

    ______________________________________                                        Weight analysis                                                                            C %         H %    N %                                           ______________________________________                                        Calculated:  66.57       6.56   6.75                                          Determined:  66.44       6.66   6.76                                          ______________________________________                                    

EXAMPLE 11 [oxo-4-(thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetonitrile C₁₅H₉ NO₂ S, (formula 11), MW=267

Prepared as in example 1 from 69.5 g (0.215 mole) ofbromomethyl-8-(thenyl-2)-2-4H-[1]-benzopyran-4-one and 28.4 g (0.42mole) of potassium cyanide. Weight obtained: 21.7 g (Yield: 40%) MP_(K): 184° C. (Ethanol).

IR: νc=0 (pyrone): 1645 cm⁻¹, νc=N: 2150 cm⁻¹.

NMR (DMSO) δ ppm compared with TMS, 2H at 4.55 (singlet), 1H at 7(singlet), 6H from 7.3 to 8.3 (multiplet).

EXAMPLE 12 [oxo-4-(thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetic acid C₁₅H₁₀ O₄ S (formula 12), MW=286.31

This preparation is prepared as in example 2 of 21.7 g (0.081 mole) of[oxo-4-thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetonitrile. After treatingwith sodium bicarbonate, a substance is obtained which is recrystallizedin dioxanne. Weight obtained: 13.9 g (Yield: 60%), MP_(G) =247°-255° C.

IR: νc=0 (pyrone): 1630 cm⁻¹, νc=0 (acid): 1710 cm⁻¹, OH: 2400-2800cm⁻¹, NMR (DMSO) δ in ppm compared with TMS, 2H at 4 (singlet), 1H at 7(singlet), 6H from 7.3 to 8.2 (multiplet), 1H at 12 (solid exchangeablewith D₂ O).

EXAMPLE 13 Methyl [oxo-4-(thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetate,C₁₆ H₁₂ O₄ S, (formula 13), MW=300.32

Substance prepared as in example 7 from 10.2 g (0.035 mole) of[oxo-4-(thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetic acid. Weight obtained:7.7 g (Yield: 68.5%), MP_(G) =168°-170° C. (methanol), IR: νc=0(Pyrone): 1645 cm⁻¹, νc=0 (ester): 1720 cm⁻¹.

    ______________________________________                                        Weight analysis:                                                                           C %         H %    S %                                           ______________________________________                                        Calculated:  63.98       4.03   10.68                                         Determined:  64.07       4.02   10.70                                         ______________________________________                                    

EXAMPLE 14 [Oxo-4-(thenyl-2)-4H-[1]-benzopyran-8-yl]acetate of (N-Ndiethylamino)-2-ethyl C₂₁ H₂₃ NO₄ S (formula 14), MW=385.45.

This substance is prepared as in example 3 from 9.6 g (0.036 mole) of[Oxo-4-(thenyl-2)-2-4H-[1]-benzopyran-8-yl]acetic acid, 2.2 g (0.033mole) of potassium hydroxide and 5 g (0.033 mole) ofchloro-2-N-N-diethylethylamine. Treatment produces an oil. Weightobtained: 12 g (Yield: 88%).

Chlorhydrate C₂₁ H₂₄ ClNO₄ S. MW=421.92. MP_(G) =210°-213° C. (ethanol).

IR: νNH+=2800-2400 cm⁻¹, νc=0 (ester)=1760 cm⁻¹, νc=0 (pyrone)=1640cm⁻¹.

MNR (CDCl₃) δ in ppm compared with TMS, 6H at 1.15 (triplet, J=7 Hz), 6Hfrom 2.7 to 3.5 (multiplet), 2H at 4.1 (singlet), 2H at 4.45 (triplet,J=6 Hz), 1H at 6.9 (singlet), 6H from 7.1 to 8 (multiplet), 1H at 10.6(exchangeable with D₂ O),

    ______________________________________                                        Analysis C %     H %     Cl %  N %   O %   S %                                ______________________________________                                        Calculated                                                                             59.80   5.73    8.40  3.31  15.16 7.60                               Determined                                                                             59.85   5.79          3.35        7.67                               ______________________________________                                    

EXAMPLE 15 [Methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetonitrileC₁₈ H₁₃ NO₂ (formula 15), MW=275.

This substance is prepared as in example 1 from 16.4 g (0.05 mole) ofbromomethyl-8-methyl-6-4H[1]-benzopyran-4-one and 6.5 g (0.01 mole) ofpotassium cyanide. Weight obtained: 11 g (Yield: 80%), MP_(K) =255° C.

IR: νc=0 (pyrone): 1630 cm⁻¹, νCN: 2250 cm⁻¹.

EXAMPLE 16 [Methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acidC₁₈ H₁₄ O₄, (formula 16), MW=294

This substance is prepared as in example 2 from 11 g (0.04 mole) of[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetonitrile. Weightobtained: 6.2 g (Yield: 53%), MP_(K) : 238°-239° C. (ethanol), IR: νc=0(pyrone): 1640 cm⁻¹, νc=0 (acid) 1710 cm⁻¹. NMR (DMSO) δ in ppm comparedwith TMS: 3H at 2.4 (singlet), 1at 3.8 (solid exchangeable with D₂ O) 2Hat 4 (singlet), 1H at 7 (singlet), 7H from 7.4 to 8.3 (multiplet).

EXAMPLE 17 Methyl[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetateC₁₉ H₁₆ O₄, (formula 17), MW=308

This substance is prepared as in example 7 from 84.7 g (0.288 mole) of[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetic acid. Weightobtained: 75 g (Yield: 84.55%, MP_(K) : 228°-230° C. IR: νc=0 (ester)1740 cm⁻¹, νc=0 (pyrone): 1638 cm⁻¹.

EXAMPLE 18 [Methyl-6-oxo-4-phenyl-[1]-benzopyran-8-yl]acetate of(N,N-diethylamino)-2-ethyl C₂₄ H₂₇ NO₄ (formula 18), MW=393.49

This substance is prepared as in example 3 from 8.5 g (0.029 mole) of[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)acetic acid and 4.73 g(0.035 mole) of chloro-2-N,N-diethylethylamine, replacing acetone by DMFand heating for 21/2 hours at 80° C. After evaporation of the DMF, theresidue is dissolved in chloroform, washed with sodium hydroxide andthen in water, dried, evaporated under vacuum and recrystallized in ahexane-toluene mixture. Weight obtained: 8.8 g (Yield: 77%), MP_(K)=120° C.,

IR: νc=0 (pyrone)=1655 cm⁻¹ ; νc=0 (ester)=1750 cm⁻¹, NMR (CDCl₃) 6H at0.92 (triplet, J=7 Hz), 9H from 2.3 to 2.9 (multiplet), 2H at 3.97(singlet), 2H at 4.2 (triplet, J=6 Hz), 1H at 6.8 (singlet), 7H from 7.2to 8.1 (multiplet).

Chlorhydrate C₂₄ H₂₈ ClNO₄. MW=429.95, MP_(G) =188°-190°(ethanol-ether).

    ______________________________________                                        Weight analysis                                                                         C %       H %    Cl %    N %  O %                                   ______________________________________                                        Calculated                                                                              64.07     6.56   8.25    3.26 14.89                                 Determined                                                                              64.34     6.35   8.27    3.46                                       ______________________________________                                    

EXAMPLE 19 Diethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2,methyl-2-malonate C₂₃ H₂₂ O₆ (formula 19), MW=394

200 ml of ethyl carbonate are put into 3.26 g (0.068 mole) of 50% sodiumhydride. The mixture is heated to 60° C. and 19 g (0.065 mole) ofmethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetate are added. It isthen taken progressively to reflux temperature and after an hour a whiteprecipitate is formed. Refluxing is continued for 2 hours and themixture is then cooled to 20° C. and, at this temperature, a solution of23 g of methyl iodide in 65 ml of dmethyl-formamide is added. This isleft stirring overnight, the precipitate is centrifuge-separated andfiltrate evaporated under vacuum, taken up in water and extracted withbenzene. After drying and evaporating the solvent, the oil obtained isrecrystallized in diisopropylether. Weight obtained: 19.3 g (Yield:75%), MP_(K) =130° C. NMR (CCl₄) δ in ppm as compared with TMS, 6H at1.2 (triplet), 3H at 2 (singlet), 4H at 4.15 (quartet), 1H at 6.85(singlet), 8H from 7.3 to 8.4 multiplet).

EXAMPLE 20 [oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2 propionic acid C₁₈H₁₄ O₄ (formula 20) MW=294

19 g (0.048 mole) of diethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2,methyl-2, malonate, 100 ml of acetic acid and 50 ml of concentratedhydrochloric acid are heated together in a reflux condenser for 7 hours.The mixture is cooled to room temperature and 50 ml of water added whilestirring. The precipitate is filtered, washed with water and taken up in500 ml of a 5% sodium bicarbonate solution. The insoluble matter isfiltered off and acidified with concentrated HCl. Weight obtained: 4.1 g(28.9%). MP_(G) =216°-218° C. IR: νc=0 (pyrone): 1640 cm⁻¹, νc=0 (acid):1740 cm⁻¹. NMR (DMSO) δ in ppm in comparison with TMS 3H at 1.65(doublet), 1H at 3.8 (exchangeable with D₂ O), 1H at 4.4 (quartet), 1Hat 7.1 (singlet), 8H from 7.4 to 8.4 (multiplet).

    ______________________________________                                        Weight analysis:   C %    H %                                                 ______________________________________                                        Calculated:        73.46  4.79                                                Determined:        73.47  4.70                                                ______________________________________                                    

EXAMPLE 21 [Oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2-propionate of(N,N-diethylamino)-2-ethyl C₂₄ H₂₇ NO₄, (Formula 21), MW=393.46

This substance is prepared as in example 3 from 3.6 g (0.012 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2-propionic acid, 0.08 g (0.012mole) of potassium hydroxide and 1.82 g (0.012 mole) ofchloro-2-N,N-diethylethylamine. An oil is obtained.

Chlorhydrate C₂₄ H₂₈ ClNO₄, MW=429.91, MP_(G) =261°-3° C. (ethanol)

IR: νNH⊕=2400-2800 cm⁻¹, νc=0 (ester)=1745 cm⁻¹, νc=0 (pyrone)=1660cm⁻¹. NMR (CDCl₃) δ in ppm as compared with TMS, 6H at 1.2 (triplet J=7Hz), 3H at 1.8 (doublet J=8 Hz), 6H from 2.4 to 3.3 (multiplet), 3H from3.4 to 3.8 (multiplet), 1H to 6.9 (singlet), 8H from 7.2 to 8.4(multiplet), 1H to 12.7 (exchangeable with D₂ O).

    ______________________________________                                        Analysis  C %       H %    Cl %    N %  O %                                   ______________________________________                                        Calculated                                                                              67.04     6.56   8.25    3.26 14.89                                 Determined                                                                              66.88     6.52           3.20                                       ______________________________________                                    

EXAMPLE 22Diethyl[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2-methyl-2,malonate C₂₄ H₂₄ O₆ (formula 22) MW=408.45

This substance is prepared as in example 19 from 31.3 g (0.1 mole) ofmethyl [methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]acetate, 325 mlof ethyl carbonate, 5.39 g (0.11 mole) of 50% sodium hydride and 37.8 gof methyl iodide. Weight obtained: 32.3 g (Yield: 77.8%), MP_(K)=147°-148° C. (diisopropylether). MNR (CDCl₃) δ in ppm as compared withTMS, 6H at 1.2 (triplet), 3H at 2.05 (singlet), 3H at 2.5 (singlet), 4Hat 4.2 (quartet), 1H at 6.8 (singlet), 7H from 7.2 to 8 (multiplet).

EXAMPLE 23 [Methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2, propionicacid C₁₉ H₁₆ O₄ (formula 23), MW=303.32

This substance is prepared as in example 20 from 32 g (0.078 mole) ofdiethyl[methyl-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-2methyl-2-malonate. Weight obtained: 8.5 g (Yield: 35%). MP_(G)=232°-234° C. (ethanol-water). NMR (DMSO) δ in ppm as compared with TMS,3H at 1.6 (doublet), 3H at 2.4 (singlet), 1H at 4.3 (quartet), 1H at 4.6(extended solid exchangeable with D₂ O), 1H at 7 (singlet), 7H at 7.4 to8.3 (multiplet).

    ______________________________________                                        Weight analysis:   C %    H %                                                 ______________________________________                                        Calculated:        74.01  5.23                                                Determined:        74.04  5.21                                                ______________________________________                                    

EXAMPLE 24 [Oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]carboxaldehyde C₁₆ H₁₀O₃ (formula 24), MW=250.26 Method A

37.2 g (0.118 mole) of bromomethyl-8-phenyl-2-4H-[1]-benzopyran-4-one,are put into a reaction vessel with 27.6 g (0.197 mole) of hexamethylenetetramine and 400 ml of chloroform. The mixture is heated for 2 h in areflux condenser, the chloroform is evaporated under vacuum and 515 mlof acetic acid are added. The mixture is then heated for 2 h underreflux and then, after filtration and the addition of 67.5 ml ofconcentrated hydrochloric acid, refluxing is continued for 30 minutes.The mixture is allowed to stand overnight. After evaporation undervacuum, the residue is recrystallized in the water/acetic acid mixture.Weight obtained: 11.6 g (Yield: 39.3%), MP_(K) : =190° C. IR: νc=0(pyrone): 1650 cm⁻¹, νc=0 (aldehyde): 1710 cm⁻¹. NMR (DMSO) δ in ppmcompared with TMS, 1H at 7.2 (singlet), 8H from 7.5 to 8.5 (multiplet),1H at 10.7 singlet).

Method B

10.85 g (0.043 mole) of hydroxymethyl-8-phenyl-2-4H[1]-benzopyran-4-one,are put in a reaction vessel with 525 ml of chloroform and 11.21 g(0.129 mole) of activated MNO₂. This is then refluxed for 6 hours. Thesolid is filtered while hot, brought to the boil again with 500 ml ofchloroform after which the chloroform solutions are mixed together andconcentrated under vacuum. The solid obtained is recrystallized in thewater/acetic acid mixture. Weight obtained: 6.1 g (Yield: 56.7%).Hydroxymethyl-8-phenyl-2-4H-[1]-benzopyran-4-one is obtained as follows:13.1 g (0.041 mole) of bromomethyl-8-phenyl-2-4H-[1]-benzopyran-4-oneare put into 104 ml of dioxanne and 104 ml of a 5% aqueous solution ofsodium bicarbonate. The mixture is heated for 2 hours under reflux,concentrated under vacuum and the residue taken up in 300 ml of water.The precipitate obtained is centrifuged, dried and recrystallized inmethanol. Weight obtained: 8 g (Yield: 77%), MP_(G) =175°-177° C. IR:νc=0 (pyrone): 1640 cm⁻¹, νOH: 3400 cm⁻¹. NMR (DMSO) δ in ppm comparedwith TMS, 2H at 5 (singlet), 1H at 5.45 (solid unchangeable by D₂ O), 1Hat 7 (singlet), 8H from 7.3 to 8.3 (multiplet).

    ______________________________________                                        Analysis:         C %    H %                                                  ______________________________________                                        Calculated:       76.17  4.80                                                 Determined:       76.54  4.60                                                 ______________________________________                                    

EXAMPLE 25 [Oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propenoic acid C₁₈H₁₂ O₄ (formula 25) MW: 292.28

A mixture of 15.8 g (0.06 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]carboxaldehyde, 12 ml of aceticanhydride and 5.3 g (0.064 mole) of anhydrous sodium acetate are heatedto 140°-145° C. for 8 hours. After cooling, the material is taken up inhot water and the precitate obtained is centrifuged and washed withwater, then brought to boiling point in a 5% sodium bicarbonatesolution, insoluble matter is filtered off and, using hydrochloric acidto acidify the solution, a precipitate is obtained which isrecrystallized in the water/acetic acid mixture. Weight obtained: 9.7 g(Yield: 52.5%); MP_(G) : 263°-265° C. IR: νc=0 (pyrone): 1640 cm⁻¹, νc=0(acid): 1710 cm⁻¹. NMR (DMSO) δ in ppm compared with TMS. 1H at 3.8(solid exchangeable with D₂ O), 1H at 6.9 (J=15 Hz, duplet), 1H at 7.1(singlet).

EXAMPLE 26Diethylamino-2-ethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propenoate,C₂₄ H₂₅ NO₄ (formula 26) MW: 391.42

This substance is prepared as in example 3 from 3.4 g (0.011 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propenoic acid, 0.77 g (0.011mole) of potassium hydroxide and 1.9 g (0.14 mole) ofdiethylamino-2-chloro-1-ethane. Weight obtained: 2.6 g (Yield: 60.3%),MP_(K) : 84° C. (hexane).

IR: νc=0 (pyrone): 1640 cm⁻¹, νc=0 (ester): 1720 cm⁻¹. NMR (CDCl₃) δ inppm compared with TMS. 6H at 1.1 (triplet), 6H from 2.4 to 3(multiplet), 2H at 4.4 (triplet), 1H at 6.8 (duplet, J: 15 Hz), 1H at 7(singlet), 9H from 7.2 to 8.4 (multiplet).

Chlorhydrate C₂₄ H₂₆ C1NO₄, MW=427.92, MP_(G) =194°-196° C.(isopropanol).

    ______________________________________                                        Weight analysis:                                                                           C %    H %       Cl %  N %                                       ______________________________________                                        Calculated:  67.36  6.12      8.29  3.27                                      Determined:  67.22  6.07      8.16  3.21                                      ______________________________________                                    

EXAMPLE 27(Morpholinyl-4)-2-ethyl[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propenoate,C₂₄ H₂₃ NO₅ (formula 27), MW=405.4

This substance is prepared as in example 3 from 8.5 g (0.03 mole) of[oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propenoic acid, 1.92 g (0.03mole) of potassium hydroxide and 5.25 g (0.035 mole) of(chloro-2-ethyl)-4-morpholine. Weight obtained: 9.5 g (Yield: 78.1%),MP_(K) =126° C. (acetone).

IR: νc=0 (pyrone): 1640 cm⁻¹, νc=0 (ester): 1720 cm⁻¹. NMR (CDCl₃) δ inppm compared with TMS, 6H from 2.5 to 3 (multiplet), 4H from 3.7 to 4(multiplet), 2H at 4.5 (triplet), 1H at 6.8 (duplet J=15 Hz), 1H at 7(singlet), 9H from 7.4 to 8.6 (multiplet).

Chlorhydrate C₂₄ H₂₄ ClNO₅, MW=441.9, MP_(G) =243°-5° C.

    ______________________________________                                        Analysis:    C %    H %       Cl %  N %                                       ______________________________________                                        Calculated:  65.23  5.47      8.02  3.17                                      Determined:  65.10  5.38      8.05  3.08                                      ______________________________________                                    

EXAMPLE 28[(Methoxy-3-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile C₁₈ H₁₃NO₃ (formula 28), MW=291.31.

This substance is prepared as in example 1 from 23.9 g (0.066 mole) of(bromomethyl)-8-(methoxy-3-phenyl)-2-4H-[1]-benzopyranone-4 and 9.1 g ofpotassium cyanide, to obtain 9.3 g of the substance with a yield of 46%.MP_(K) =170° C. IR: νc=0=1650 cm⁻¹. NMR (DMSO), 3H at 3.9 (singlet), 2Hat 4.5 (singlet), 8H from 6.9 to 8.3 (multiplet).

EXAMPLE 29 [(Methoxy-3-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]aceticacid C₁₈ H₁₄ O₅ (formula 29), MW=310.31

This substance is prepared as in example 2 from 9.1 g (0.031 mole) of[(methoxy-3-phenyl)-2-oxo-4-4H-[1]-benzoyran-8-yl]-acetonitrile. Weightobtained: 2.2 g. MP_(G) =238°-241° (MiBK), IR: νc=0 (pyrone)=1635 cm⁻¹ ;νc=0 (acid)=1710 cm⁻¹. NMR (DMSO), 1H at 3.4 (exchangeable with D₂ O),3H at 3.9 (singlet), 2H at 4.02 (singlet), 1H at 7.1 (singlet), 7H from7.1 to 8.1 (multiplet).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  69.67       4.55   25.78                                         Determined:  69.91       4.61                                                 ______________________________________                                    

EXAMPLE 30 (Methoxy-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)acetonitrileC₁₈ H₁₃ NO₃, (formula 30), MW=291.31

This substance is prepared as in example 1 from 30 g (0.087 mole) ofbromomethyl-8-methoxy-6-phenyl-2-4H-[1]-benzopyranone-4 and 11.9 g ofpotassium cyanide. Since the substance is insoluble when hot, it is notfiltered when hot but is cooled, filtered cold, washed water and dried.Weight obtained: 15.9 g (Yield: 62%), MP_(K) =270° C., IR: νc=0=1635cm⁻¹. The substance is not soluble enough to obtain an NMR spectrum.

EXAMPLE 31 (Methoxy-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)acetic acidC₁₈ H₁₄ O₅ (formula 31) MW=310.31

This substance is prepared as in example 2 from 8 g (0.027 mole) of(methoxy-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)acetonitrile. Weightobtained: 3.7 g, IR: νc=0 (pyrone)=1630 cm⁻¹ ; νc=0 (acid): 1720 cm⁻¹νOH=2400 to 3500 cm⁻¹. The NMR shows that a mixture of the substance inthe title and (hydroxy-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)aceticacid (formula 32) has been obtained. This mixture is used as such in thefollowing example.

EXAMPLE 32 (Methoxy-6-oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)acetate of(N,N-diethylamino)-2-ethyl C₂₄ H₂₇ NO₅, (formula 33) MW=409.49

This substance is prepared as in example 3 from 3.5 g of the acidmixture from example 31 and 1.84 g (0.013 mole) ofchloro-2-N,N-diethylethylamine, replacing acetone by DMF, and heatingfor 21/2 hours at 80° C. After evaporation, the solid is taken up in CH₂Cl₂, washed with N sodium hydroxide, then with water, dried andevaporated under vacuum. Weight obtained: 1.4 g. NMR (CDCl₃), 6H at 0.95(triplet, J=7 Hz), 6H from 2.3 to 2.8 (multiplet), 3H at 3.9 (singlet),2H at 3.96 (singlet), 2H at 4.2 (triplet, J=6 Hz), 1H at 6.8 (singlet),7H from 7.1 to 8.1 (multiplet).

EXAMPLE 33[(Dimethoxy-3,4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile C₁₉H₁₅ NO₄ (formula 34) MW =321.34

This substance is prepared as in example 1 from 30 g (0.080 mole) of(bromomethyl)-8-(dimethoxy-3,4-phenyl)-2-4H-[1]-benzopyranone-4 and 11 gof potassium cyanide. Weight obtained: 10.5 g (Yield: 40%). MP_(K) =226°C., IR: νc=0 (pyrone)=1650 cm³¹ 1 ; νc=N=2260 cm⁻¹. The substance is notsoluble and apt to obtain an NMR spectrum.

EXAMPLE 34 [(dimethoxy-3,4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]aceticacid C₁₉ H₁₆ O₆ (formula 35) MW=340.34.

This substance is prepared as in example 2 from 10.2 g (0.032 mole) of[(dimethoxy-3,4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile.Weight obtained: 3.9 g, MP_(G) =250°-254° (AcOH), IR: νc=0 (pyrone)=1645cm⁻¹ ; νc=0 (acid)=1720 cm⁻¹. NMR (DMSO), 3H at 3.83 (singlet), 3H at3.9 (singlet), 2H at 4.03 (singlet), 7H from 6.8 to 8.1 (multiplet), 1Hat 12 (exchangeable with D₂ O).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  67.05       4.74   28.21                                         Determined:  67.16       4.68                                                 ______________________________________                                    

EXAMPLE 35Diethyl[(Oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl)methyl]-2-propanedioateC₂₃ H₂₂ O₆ (formula 36) MW=390.24

Starting from a suspension of 2.3 g (0.1 mole) of sodium pellets in 100ml of anhydrous benzene, 15.6 g (0.1 mole) of diethyl propanedioate isadded at room temperature and heated for 5 hours in a reflux condenser,then left for 12 hours with stirring at room temperature. A solution of31.5 g (0.1 mole) of bromomethyl-8-phenyl-2-4H-[1]-benzopyranone-4 in300 ml of benzene is then added. The mixture is heated for 7 hours withreflux. After filtration and evaporation of the solvent, a white solidis isolated which is recrystallized. Weight obtained: 26 g (Yield: 66%),MP_(G) =87°-90° C. (ethanol), IR: νc=0 (ester)=1740 cm⁻¹, νc=0(pyrone)=1650 cm⁻¹.

EXAMPLE 36 [Oxo-4-phenyl-2-4H-[1]-benzopyran-8-yl]-3-propionic acid C₁₈H₁₄ O₄ (formula 37), MW=294.29

A solution of 26 g (0.066 mole) ofdiethyl[(oxo-4phenyl-2-4H-[1]benzopyran-8-yl)methyl]-2-propanedioate isheated in a reflux condenser for 7 hours with 93 ml of acetic acid and46 ml of concentrated hydrochloric acid. The reacting mixture is pouredinto 800 ml of water and, after filtration, treated with 5% sodiumbicarbonate solution. 10.5 g of the substance are obtained (Yield: 53%).MP_(G) =201°-202° C. (acetone/ethanol) IR: νOH (acid)=2800-3300 cm⁻¹νc=0 (acid)=1740 cm⁻¹, νc=0 (pyrone)=1640 cm⁻¹. NMR (CDCl₃) δ in ppmcompared with TMS, 2H at 2.6 (triplet J=7 Hz), 2H at 3.2 (triplet J=7Hz), 1H at 7 (singlet), 8H from 7.2 to 8.2 (multiplet), 1H at 12.1(exchangeable with D₂ O).

    ______________________________________                                        Analysis:   C %          H %    O %                                           ______________________________________                                        Calculated: 73.46        4.80   21.74                                         Determined: 73.52        4.55                                                 ______________________________________                                    

EXAMPLE 37 [(Furyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile C₁₅ H₉NO₃ (formula 38), MW=251.22

This substance is prepared as in example 1 from 23.4 g (0.077 mole) ofbromomethyl-8-(furyl-2)-2-4H-[1]-benzopyranone-4 and 10 g (0.154 mole)of potassium cyanide. Weight obtained: 15.5 g (Yield: 83%). MP_(K) =195°C. (ethanol). IR νc=N=2250 cm⁻¹, νc=0 (pyrone): 1650 cm⁻¹.

EXAMPLE 38 [(furyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]-acetic acid C₁₅H₁₀ O₅ (formula 39), MW=270.23

This substance is prepared as in example 2 from 16 g (0.063 mole) of[(furyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile. Weight obtained:8.5 g (Yield: 49%). MP_(G) =240°-2° C. IR: OH=2800-3200 cm⁻¹, νc=0(acid)=1720 cm⁻¹, νc=0 (pyrone)=1650 cm⁻¹. NMR (DMSO) δ in ppm comparedwith TMS, 2H at 4 (singlet), 1H at 6.7 (singlet), 1H from 6.8 to 7(multiplet), 5H from 7.3 to 8.1 (multiplet), 1H at 12.6 (exchangeablewith D₂ O).

    ______________________________________                                        Analysis:   C %          H %    O %                                           ______________________________________                                        Calculated: 66.67        3.73   29.60                                         Determined: 66.81        3.74                                                 ______________________________________                                    

EXAMPLE 39[(Methyl-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile C₁₈ H₁₃NO₂ (formula 40), MW=275.30

This substance is prepared as in example 1 from 33 g (0.1 mole) ofbromomethyl-8-(methyl-4-phenyl-)-2-4H-[1]-benzopyranone-4 and 13 g (0.2mole) of potassium cyanide. Weight obtained: 23.5 g (Yield: 85.5%).MP_(K) =190° C.

IR: νc=N=2160 cm⁻¹, νc=0 (pyrone)=1640 cm⁻¹.

EXAMPLE 40 [(methyl-4-phenyl-)-2-oxo-4-4H-[1]-benzopyran-8-yl]aceticacid C₁₈ H₁₄ O₄ (formula 41), MW=294.29

This substance is prepared as in example 2 from 23.5 g (0.085 mole) of[(methyl-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile. Aftertreatment with sodium bicarbonate and recrystallization in acetic acid,15 g of the substance are obtained. (Yield: 59%. MP_(G) =250-252° C.

IR: νOH=2800-3200 cm⁻¹, νc=0 (acid)=1720 cm⁻¹, νc=0 (pyrone)=1630 cm⁻¹.NMR (DMSO) δ in ppm compared with TMS, 3H at 2.2 (singlet), 2H at 4(singlet), 1H at 7 (singlet), 7H from 7.2 to 8.1 (multiplet) 1H at 12.7(exchangeable with D₂ O).

    ______________________________________                                        Analysis:   C %          H %    O %                                           ______________________________________                                        Calculated: 73.46        4.80   21.74                                         Determined: 73.77        4.94                                                 ______________________________________                                    

EXAMPLE 41 [(Methyl-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetate of(N,N-diethylamino)-2ethyl, C₂₄ H₂₇ NO₄ (formula 42), MW=393.46

This substance is prepared as in example 3 from 16.4 g (0.0557 mole) of[(methyl-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetic acid, 3.67 g(0.0557 mole) of potassium hydroxide and 8.27 g (0.061 mole) ofchloro-2-N,N-diethylethylamine. 15 g (Yield: 70%) of a white solid areobtained. MP_(G) =87°-89° C. (diisopropylether).

Chlorhydrate C₂₄ H₂₈ ClNO₄, MW=429.91, MP_(G) =175°-177° C. (ethanol),IR: νNH+=2400-2800 cm⁻¹, νc=0 (ester)=1750 cm⁻¹, νc=0 (pyrone)=1640cm⁻¹. RMN (CDCl₃) δ in ppm compared with TMS, 6H at 1.3 (triplet, J=7Hz), 3H at 2.5 (singlet), 6H from 2.7 to 3.4 (multiplet), 2H at 4.2(singlet), 2H at 4.7 (triplet, J=6 Hz), 1H at 6.8 (singlet), 7H from 7.2to 8.4 (multiplet), 1H at 12.7 (exchangeable with D₂ O).

    ______________________________________                                        Analysis:  C %      H %    Cl %    N %  O %                                   ______________________________________                                        Calculated:                                                                              67.04    6.56   8.25    3.26 14.89                                 Determined:                                                                              67.30    6.67           3.36                                       ______________________________________                                    

EXAMPLE 42 [(Naphtyle-2-)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrileC₂₁ H₁₃ NO₂ (formula 43), MW=311.31

This substance is prepared as in example 1 from 61 g (0.167 mole) ofbromomethyl-8-naphtyl-2)-2-4H-[1]-benzopyranone-4 and 21.8 g (0.344mole) of potassium cyanide. 43 g (yield: 84%) are obtained. MP_(K) =189°C. (ethanol).

IR: νc=N=2260 cm⁻¹, νc=0 (pyrone)=1660 cm⁻¹.

EXAMPLE 43 [(Naphtyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetic acid C₂₁H₁₄ O₄ (formula 44), MW=330.32.

This substance is prepared as in example 2 from 43.5 (0.14 mole) of[(naphtyl-2)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile. Byrecristallizing in acetic acid, 29 g of substance are obtained (yield:62.7%). MP_(G) =225°-228° C., IR=νOH=2400-2800 cm⁻¹, νc=0 (acid)=1720cm⁻¹, νc=0 (pyrone)=1640 cm⁻¹. NMR (DMSO) δ in ppm compared with TMS, 2Hat 4 (singlet), 1H at 7.1 (singlet), 10H from 7.2 to 8.2 (multiplet), 1Hat 12.6 (exchangable with D₂ O).

    ______________________________________                                        Analysis:   C %          H %    O %                                           ______________________________________                                        Calculated: 76.35        4.27   19.38                                         Determined: 76.25        4.15                                                 ______________________________________                                    

EXAMPLE 44[(Methoxy-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]actonitrile C₁₈ H₁₃NO₃ (formula 45), MW=291.28

This substance is prepared as in example 1 from 34.5 g (0.1 mole) ofbromomethyl-8-(methoxy-4-phenyl)-2-4H-[1]-benzopyranone-4 and 13 g (0.2mole) of potassium cyanide. 25.3 g are obtained (yield: 87%). MP_(K)=190° C. (ethanol), IR: νc=N=2250 cm⁻¹, νc=0 (pyrone)=1640 cm⁻¹.

EXAMPLE 45 [(Methoxy-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]aceticacid C₁₈ H₁₄ O₅, (formula 46), MW32 310.29

This substance is prepared as in example 2 from 25.3 g (0.087 mole) of[(methoxy-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile. Weightobtained: 23.6 g (yield: 87.4%). MP_(G) =228°-232° C. (acetic acid). IR:νOH=2400-2800 cm⁻¹, νc=0 (acid)=1720 cm⁻¹, νc=0 (pyrone)=1640 cm⁻¹. NMR(DMSO) δ en ppm compared with TMS, 3H at 3.9 (singlet), 2H at 4.1(singlet), 8H from 7 to 8.3 (multiplet), 1H at 12.7 (exchangable with D₂O).

    ______________________________________                                        Analysis:   C %          H %    O %                                           ______________________________________                                        Calculated: 69.67        4.55   25.78                                         Determined: 69.64        4.58                                                 ______________________________________                                    

EXAMPLE 46 [(Methoxy-4-phenyl)-2-oxo-4-4H-[1]-benzopran-8-yl]acetate of(N,N-diethylamino)-2-ethyl, C₂₄ H₂₇ NO₅ (formula 47), MW=409.46

This substance is prepared as in example 3 from 17.3 g (0.0557 mole) of([methoxy-4-phenyl)-2-oxo-4-4H-[1]-benzopyran-8-yl]-acetic acid, 3.67 g(0.0557 mole) of potassium and 8.27 (0.061 mole) ofchloro-2-N,N-diethylethylamine. After processing, a solid is obtainedwhich is recristallized in di-isopropylether. Weight obtained: 16 g(yield: 70%). MP_(K) =120° C.

Chlorhydrate C₂₄ H₂₈ ClNO₅, MW=445.91, MP_(G) =161°-163° C., IR:νNH+=2400-2800 cm⁻¹, νc=0 (ester)=1750 cm⁻¹, νc=0 (pyrone): 1640 cm⁻¹.NMR (CDCl₃) δ in ppm compared with TMS, 6H at 1.3 (triplet, J=7 Hz), 6Hfrom 2.8 to 3.4 (multiplet), 3H at 3.95 (singlet), 2H at 4.2 (singlet),2H at 4.65 (triplet, J=6 Hz), 1H at 6.8 (singlet), 7H from 7 to 8.2(multiplet), 1H at 12.7 (exchangable with D₂ O).

    ______________________________________                                        Analysis:  C %      H %    Cl %    N %  O %                                   ______________________________________                                        Calculated:                                                                              64.64    6.33   7.95    3.14 17.94                                 Determined:                                                                              64.50    6.41           3.02                                       ______________________________________                                    

EXAMPLE 47 [Cyclohexyl-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile C₁₇H₁₇ NO₂ (formula 48) MW=267.33

This substance is prepared as in example 1 from 15.2 g (0.047 mole) ofbromo-methyl-8-cyclohexyl-2-4H-[1]-benzopyranone-4 and 6.2 g (0.095mole) of potassium cyanide. When the reaction is completed, thesubstance is evaporated under vacuum, taken up with water, extractedwith chloroform, dried and evaporated under vacuum. Weight obtained:12.4 g (yield: 98%) (oil). IR: νc=N=2240 cm⁻¹ ; νc=0 (pyrone)=1650 cm⁻¹l NMR (CDCl₃), 11H from 1.0 to 3.0 (multiplet), 2H at 3.9 (singlet), 1Hat 6.2 (singlet), 2H from 7.2 to 7.9 (multiplet), 1H at 8.15 (doubleduplet, J₁ =8 Hz, J₂ =2 Hz).

EXAMPLE 48 [Oxo-4-(phenylmethyl)-2-4H-[1]-benzopyran-8-yl]acetonitrileC₁₈ H₁₃ NO₂ (formula 49), MW=275.31

This substance is prepared as in example 1 from 47 g (0.143 mole) ofbromomethyl-8-(phenylmethyl-2-4H-[1]-benzopyranone-4 and 18.5 g (0.284mole) of potassium cyanide. After filtration while hot it is evaporatedunder vacuum and recristallized in an ethanol/water mixture. Weightobtained: 7.1 g (yield: 18%), MP_(K) =100° C. IR: νc=N=2240 cm⁻¹ ; νc=0(pyrone)=1640 cm⁻¹. NMR (CDCl₃), 2H at 3.83 (singlet), 2H at 3.97(singlet), 1H at 6.2 (singlet), 7H from 7.2 to 7.8 (multplet), 1H at 8.2(double duplet, J₁ =8 Hz, J₂ =2 Hz).

EXAMPLE 49 Oxo-4-phenyl-3-4H-[1]-benzopyran carboxaldehyde-8 C₁₆ H₁₀ O₃(formula 50) MW=250.26

This substances is prepared as in example 24 from 88.2 g (0.28 mole) ofbromo-methyl-8-phenyl-3-4H-[1]-benzopyranone-4 with the followingdifferences: after adding, the hydrochloric acid, no heat is applied butthe mixture is shaken overnight at ambient temperature and then filteredto remove insoluble substances. The filtrate is diluted with water andthe precipitate thus obtained is filtered. Weight obtained: 52.4 g(yield: 74%). MP_(K) =162° C. (AcOEt), IR: νc=0 (pyrone)=1650 cm⁻¹, νc=0(aldehyde)=1700 cm⁻¹. NMR (CDCl₃) 6H from 7.2 to 7.8 (multiplet), 1H at8.12 (singlet), 1H at 8.3 (double duplet, J₁ =8 Hz, J₂ =2 Hz), 1H at 8.6(double duplet, J₁ =8 Hz, J₂ =2 Hz), 1H at 10.7 (singlet).

EXAMPLE 50 (Cyclohexyl-2-oxo-4-4H-[1]-benzopyran-8-yl)acetic acid, C₁₇H₁₈ O₄ (formula 51), MW=286.33

This substance is prepared from 12.4 g (0.046 mole) of(cyclohexyl-2-oxo-4-4H-[1]-benzopyran-8-yl]acetonitrile. After dilutionwith water, extraction with chloroform, washing with water andevaporation under vacuum, it is dissolved in a 5% aqueous solution ofsodium bicarbonate, the insoluble matter filtered out, cooled,acidified, filtered and recristallized in toluene. Weight obtained: 3.4g (yield: 25%). MP_(G) =180°-182° C. IR: νc=0 (pyrone)=1645 cm⁻¹, νc=0(acid)=1700 cm⁻¹. NMR (DMSO), 11H from 1.0 to 3.0 (multiplet), 2H at3.87 (singlet), 1H at 6.2 (singlet), 1H at 7.4 (triplet, J=8 Hz), 1H at7.72 (double duplet, J₁ =8 Hz, J₂ +2 Hz), 1H at 7.97 (double duplet, J₁=8 Hz, J₂ =2 Hz).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  71.31       6.34   22.35                                         Determined:  71.48       6.35                                                 ______________________________________                                    

EXAMPLE 51 (Oxo-4-phenyl-3-4H-[1]-benzopyran-8-yl)acetic acid, C₁₇ H₁₂O₄, (formula 52), MW=280.28

A mixture of 4.8 g (0.1 mole) of a 50% suspension of sodium hydride inoil and 120 ml of anhydrous dioxane has added to it drop by drop asolution of 33.1 g (0.1 mole) of tetraethyl dimethylaminomethylenediphosphonate (C. R. Degenhardt, Synth. Commun. 1982, 12, 415) in 120 mlof dioxane. This is stirred for one hour at 25° C., and then a solutionof 25 g (0.1 mole) of oxo-4-phenyl-3-4H-[1]-benzopyrancarboxaldehyde-8in 120 ml of dioxane is added drop by drop. This is heated to 50° C. forone hour, then evaporated under vacuum, taken up in water, extracted inchloroform and evaporated under vacuum. The residue is taken up with 1.5l of concentrated hydrochloric acid and heated with reflux for 30 min.It is cooled, diluted with iced water, extracted with chloroform, washedwith water, dried and evaporated under vacuum. The residue is taken upwith 300 ml of a 5% aqueous solution of sodium bicarbonate using areflux, filtered, the filtrate is cooled and acidified (6N HCl). Thepasty precipitate obtained is extracted with chloroform, dried andevaporated under vacuum. The residue is purified by chromotography(SiO₂, C₆ H₆ -AcOH-MeOH-45:8:8), then recristallized in toluene. Weightobtained: 1.1 g. MP_(G) =137°-139° C.

IR: νc=0 (pyrone)=1640 cm⁻¹ ; νc=0 (acid)=1730 cm⁻¹. NMR (CDCl₃), 2H at3.97 (singlet), 7H from 7.1 to 7.8 (multiplet), 1H at 8.05 (singlet), 1Hat 8.3 (double duplet, J₁ =8 Hz, J₂ =2 Hz), 1H at 8.8 (exchangable withD₂ O).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  72.85       4.32   22.83                                         Determined:  72.83       4.50                                                 ______________________________________                                    

EXAMPLE 52 [Oxo-4-(phenylmethyl)-2-4H-[1]-benzopyran-8-yl]acetic acid,C₁₈ H₁₄ O₄, (formula 53), MW=294.31

This substance is prepared as in example 2 from 7 g (0.25 mole) of[oxo-4-(phenylmethyl)-2-4H-[1]-benzopyran-8-yl]acetonitrile. Weightobtained: 2.7 g (yield: 36%). MP_(G) =143°-145° C. (toluene). IR: νc=0(pyrone)=1640 cm⁻¹ ; νc=0 (acid)=1720 cm⁻¹. NMR (CDCl₃), 2H at 3.87(singlet), 2H at 3.93 (single), 1H at 6.27 (singlet), 9H from 7.0 to 8.3(multiplet).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  73.46       4.79   21.75                                         Determined:  73.40       4.82                                                 ______________________________________                                    

EXAMPLE 53 (Diphenyl-2,3-oxo-4-4H-[1]-benzopyran-8-yl)acetonitrile, C₂₃H₁₅ NO₂, (formula 54), MW=337.38

This substance is prepared as in example 1 from 22.5 g (0.057 mole) ofbromomethyl-8-diphenyl-2,3,-4H-[1]-benzopyranone-4 and 7.6 g ofpotassium cyanide. Weight obtained: 7.1 g (yield: 36%). MP_(K) =185° C.IR: νc=0 (pyrone)=1630 cm⁻¹. NMR (CDCl₃), 2H at 4.0 (singlet), 12H from7.0 to 8.0 (multiplet), 1H at 8.3 (double duplet, J₁ =8 Hz, J₂ =2 Hz).

EXAMPLE 54 (Diphenyl-2,3-oxo-4-4H-[1]-benzopyran-8-yl) acetic acid, C₂₃H₁₆ O₄, (formula 55), MW=356.38

This substance is prepared as in example 2 from 7.1 g (0.021 mole) of(diphenyl-2,3-oxo-4-4H-[1H]-benzopyran-8-yl)acetronitrile. Weightobtained: 2.4 g MP_(G) =220°-224° C. IR: νc=0 (acid)=1730 cm⁻¹, νc=0(pyrone)=1630 cm⁻¹, νOH=2900 to 3600 cm⁻¹. NMR(DMSO), 1H at 3.5(exchangable with D₂ O), 2H at 4.0 (singlet), 13H from 7.0 to 8.3(multiplet).

    ______________________________________                                        Weight analysis:                                                                           C %         H %    O %                                           ______________________________________                                        Calculated:  77.51       4.53   17.96                                         Determined:  77.29       4.51                                                 ______________________________________                                    

EXAMPLE 55 (Methyl-2-oxo-4-4H-[1]-benzopyran-8-yl)acetonitrile, C₁₂ H₉NO₂, (formula 56), MW=199.21

This substance is prepared as in example 1 from 8.8 g (0.034 mole) ofbromo-methyl-8-methyl-2-4H-[1]-benzopyranone-4. Weight obtained: 5.1 g.

IR: νc=N=2250 cm⁻¹, νc=0 (pyrone)=1650 cm⁻¹. NMR (CDCl₃), 3H at 2,4(singlet), 2H at 3.97 (singlet), 1H at 6.2 (singlet) 1H at 7.4 (triplet,J=8 Hz, 1H at 7.7 (double duplet, J₁ =8 Hz, J₂ =2 Hz), 1H at 8.2 (doubleduplet, J₁ =8 Hz, J₂ =2 Hz).

EXAMPLE 56 (Methyl-2-oxo-4-4H-[1]-benzopyran-8-yl)acetic acid, C₁₂ H₁₀O₄, (formula 57), MW=218.21

This substance is prepared as in example 2 from 5 g (0.025 mole) of(methyl-2-oxo-4-4H-[1]-benzopyran-8-yl)acetonitrile. After treatmentwith sodium bicarbonate and acidification, the substance is purified bychromotography. (SiO₂, C₆ H₆ -CH₃ -COOH-MeOH, 45:8:8) and thenrecristallized in a water/acetic acid mixture. Weight obtained: 0.6 g.MP_(G) =230°-233° C. IR: νc=0 (acid)=0 (acid)-1720 cm⁻¹, νc=0(pyrone)=1635 cm⁻¹, νc=0 (pyrone)=2300 to 3300 cm⁻¹. NMR (DMSO), 3H at2.36 (singlet), 1H at 3.4 (exchangeable with D₂ O), 2H at 3.83(singlet), 1H at 6.25 (singlet), 1H at 7.4 (triplet, J=8 Hz), 1H at 7.7(double duplet, J₁ =8 Hz, J=2 Hz), 1H at 7.9 (double duplet, J₁ =8 Hz,J₂ =2 Hz).

We claim:
 1. (Oxo-4-4H-(1-benzopyran-8-yl)alkanoic acid, described bythe formula ##STR9## in which AR is a phenyl radical, phenyl substitutedby lower alkyl, or lower alkoxy; B is a lower linear or branchedalkylene or alkenylene radical; R₁ is hydrogen or a phenyl radical, X ishydrogen or a lower alkyl or alkoxy radical and n=1, or an alkali metalsalt thereof.
 2. An ester of the compounds according to claim 1,described by the formula ##STR10## where AR, B, R₁, X and n have thesame meanings as before, R₂ is a lower alkyl, a lower hydroxyalkyl, alower dialkylamino lower alkyl, or morpholinoethyl radical.
 3. Acompound according to claim 2 wherein R₂ is lower alkyl or hydroxy loweralkyl.
 4. An amido of the compounds described in claim 1 described bythe formula ##STR11## where AR, B, R₁, n and X have the same meanings aspreviously, and R₃ is a dialkylaminoalkyl radical. 5.(Oxo-4-4H-(1)-benzopyran-8-yl)alkanoic acid or an ester thereof, havingthe formula: ##STR12## in which AR is phenyl substituted by lower alkylor lower alkoxy, B is a lower linear or branched alkyenylene or alkyleneradical; R₁ is hydrogen or phenyl; X is hydrogen, lower alkyl or loweralkoxy; n=1; R₂ is hydrogen when the compound is an alkanoic acid; R₂ isa lower alkyl, a lower hydroxy alkyl, a lower dialkylamino lower alkyl,or a morpholinoethyl when the compound is an ester; or an alkali metalsalt of said acid.
 6. An anti-tumor composition containing an anti-tumoreffective amount of an acid according to claim 1, having the formula##STR13## wher AR is a phenyl radical, phenyl substituted by lower alkylor lower alkoxy, B is a linear or branched lower alkylene radical; R₁ ishydrogen or a phenyl radical, X is hydrogen or a lower alkyl or alkoxyradical and n=1, or alkali metal salts thereof along with apharmaceutically acceptable carrier.
 7. An anti-tumor compositioncontaining an anti-tumor effective amount of a compound according toclaim 2, along with a pharmaceutically acceptable carrier.
 8. Ananti-tumor composition containing an anti-tumor effective amount of anamide according to claim 4 along with a pharmaceutically acceptablecarrier.
 9. An anti-tumor composition comprising an anti-tumor effectiveamount of a compound according to claim 5, together with apharmaceutically acceptable carrier therefor.